All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Viruses, the ultimate parasites, usurp many cellular functions for their multiplication [Munther et al., Science's STKE 335:1-13 (2006)]. As soon as they bind to cells they trigger multiple cascades of events that they employ for cell entry, trafficking and disassembly, before they start utilizing cellular machinery for expression and replication. Some of the factors activated by the infecting virus participate in key processes such as inflammatory response and cell death.
The very early events that occur before disassembly and expression of the viral genome are most likely triggered by the viral outer shell. Thus viral capsids may be used to activate cellular mechanisms that may have therapeutic effects.
SV40 (and other members of the polyomavirus and papilloma virus families) induce chaperones following infection [Ioannis et al., FEBS Letters 355:282-286 (1994); Cripe et al., J. Virol. 69:7807-7813 (1995); Chromy et al., PNAS 100:10477-10482 (2006) and references therein], presumably because they utilize host chaperons for disassembly (and assembly). As surprisingly shown by the present invention, chaperones are induced by the capsid proteins, or the viral structural proteins, rather than by viral regulatory proteins. Chaperons were proposed to ameliorate critical conditions such as ARDS (acute respiratory distress syndrome) and AKI (Acute Kidney Injury), which was previously referred to as ATN (acute tubular necrosis). In particular, ectopic expression of HSP70, applied by gene therapy to model ARDS rats, showed ameliorating effect [Weiss et al., the J. Clin. Invest. 110:801-806 (2002)]. Therefore, the inventors examined the possibility that induction of chaperones by SV40 may serve to treat these conditions. As clearly shown by the present invention, SV40 capsids (VLPs) remarkably ameliorated pathological symptoms using the AKI mice model, and are therefore applicable for use in the treatment of Acute Renal Failure (ARF). This particular example (ARF) clearly establishes the feasibility of using viral capsid proteins, and specifically the SV40 VP1, for treating any other disorders associated with disfunction of cellular quality control mechanisms, in variety of organs.
It is therefore one object of the invention to provide viral capsid proteins VP1, VP2 and VP3, preferably, the SV40 VP1 or any peptide, mutant, fragment and mixture thereof as the active ingredient in compositions for use in the treatment of pathologic disorders, preferably disorders associated with inactivation of cellular proteins. Such cellular proteins are preferably proteins involved with quality control processes, for example, chaperones.
In yet another object the invention provides methods for the treatment of disorders associated with inactivation of cellular proteins, preferably proteins involved with quality control processes, for example, chaperones.
Another object of the invention is to provide methods for enhancing the ameliorating effect of cellular proteins involved with quality control processes, for example, chaperones, on pathologic disorders, by augmenting these cellular proteins.
In another object, the invention provides the use of SV40 capsid proteins, or SV40 VLP's comprising said capsid proteins, in the preparation of compositions for the treatment of pathologic disorders, preferably, immune-related disorders or neurodegenerative disorders.
These and other objects of the invention will become apparent as the description proceeds.